Abstract We have identified genetic variants within the IL6 and NKG2 pathways that influence outcomes disparities after unrelated donor hematopoietic cell transplantation (HCT). Patient and donor variants for the IL6ST subunit are associated with increased risk of GVHD and mortality particularly in patients of African and Hispanic ancestry, compared to patients of Asian and Caucasian ancestry. Information on both IL6ST as well as IL6R demonstrate that risks are imparted by ancestry-specific coding and regulatory variants that affect the type and quantity of proteins produced. The second genetic system, NKG2, also plays a critical role in allorecognition in HCT. Recipient HLA-E and MICA ligands together with donor NKG2A, NKG2C, NKG2D receptors are highly polymorphic and differ by ancestry. Together, both models showcase the importance of understanding the ligand and its receptor, to fully clarify their clinical importance. Information on the contribution of IL6 and NKG2 systems to clinical outcome will elucidate the risks traditionally associated with donor-recipient HLA matching. We will test novel hypotheses in three aims: 1) define the impact of IL6ST and IL6R variation on expression and HCT outcome; 2) define NKG2 ligand-receptor features that influence HCT outcomes, and 3) estimate the risks associated with HLA mismatching in HCT. Information on haplotype content and expression in ethnically- diverse transplant populations will significantly advance understanding of outcomes disparities in US transplants.